The tears of the eye are made up of three layers, an oil layer, a water layer and a mucin layer, and the tear film has the three layered structure. Dry eye syndrome or dry eye diseases (hereinafter referred to as ‘dry eye’) come in a wide range of concepts, and in many cases, its cause is not known, and thus, dry eye is defined, rather than a disease, as an abnormal condition of eyes resulting from an unstable tear film caused by a decrease or change in quantity or quality of tears and the tear film breaking up faster than normal.
According to the definition, categories of dry eyes include diseases such as keratoconjunctivitis sicca, keratoconjunctival epithelial disorder, reduced lacrimal fluid secretion, Stevens-Johnson syndrome, dry eye syndrome, Sjögren's syndrome, tear deficiency, ocular hyperemia, tear film instability, or eye edema. Furthermore, categories of dry eyes include allergic conjunctivitis, viral conjunctivitis, or dry eyes after cataract surgery. Furthermore, recently, with the increasing number of contact lens wearers, spending time in artificial air-controlled environment, and opportunity to see visual display terminals (VDT) with the wide use of TVs and computers, factors that promote dry eyes drastically increased, and as a result, categories of dry eyes include contact lens wear-related dry eyes or VDT operation-related dry eyes.
Furthermore, those with dry eyes have, in many cases, disorder with keratoconjunctivitis sicca. Particularly, when there is a tear deficiency in in the mucus layer, corneal damage is serious, causing keratoconjunctival epithelial disorder, and categories of keratoconjunctival epithelial disorder include dry eyes, corneal epithelial defect, conjunctival epithelial defect, corneal epithelial erosion, reduced corneal thickness, corneal infiltrate, corneal perforation or corneal epithelial exfoliation, and the keratoconjunctival epithelial disorder results in corneal ulcer, keratitis, conjunctivitis, superficial punctate keratopathy, keratoconjunctivitis sicca, superior limbic keratoconjunctivitis, filamentary keratitis, corneal ulcer and infectious eye diseases of corneal and conjunctival epithelium. The keratoconjunctival epithelial disorder may be caused by injury in eye, microsurgery or hard contact lens wear.
Treatment of dry eyes focuses on allowing for the maintenance of at least a predetermined volume of tears by a conservative method such as replenishing artificial tear eye drops or blocking the lacriminal ducts temporarily or eternally, but recently, with the expansion of treatment concept, the trend of dry eye treatment moves toward active treatment using drugs which promote the secretion of lacrimal fluid even for mild dry eyes, rather than passive treatment for the purpose of syndrome alleviation. In keeping with this trend, the use of immunosuppressive agents to treat dry eyes becomes more frequent. The immunosuppressive agent includes cyclosporine, sirolimus, tacrolimus and their derivatives. Among them, one of the commercially available drugs is cyclosporine A 0.05% emulsion form eye drops (Restasis®). This is known as being effective in treating dry eye syndrome and its related keratoconjunctival epithelial disorder, but at the same time, is known as causing many side effects, and the most common abnormal reaction is burning sensation in eyes, and conjunctival hyperaemia, eye discharge, epiphora, eye pain, a foreign body sensation, pruritus, a sharp, stabbing sensation, vision impairment (often blurred vision) in some patients have been reported. According to the essay whose author is Ji Eun Lee et al., as a result of contact with 0.05% cyclosporine for 10 minutes, increased apoptosis and reduced cell viability was seen, and to use without toxic effect of corneal epithelial cells, the duration of exposure to 0.05% cyclosporine should be less than 10 minutes (J Korean Ophthalmol Soc 48(10):1399-1409, 2007), and cell viability significantly reduced at 0.05% (5 μg/mL) or more of cyclosporine (Graefe's Arch Clin Exp Ophthalmol (2006) 244: 382-389).
In addition to cyclosporine, the use of an excessive amount of immunosuppressive agents causes side effects such as anemia, leukopenia, thrombocytopenia, and hair loss. However, in keeping with the recent trend, for treatment of severe dry eyes as well as clinical symptoms of discomfort even in mild cases, immunosuppressive agents are actively used to treat dry eyes. Further, generally, patients with dry eyes have many drug types and frequent doses, and it is known that these factors reduce drug compliance and treatment effect.
On the other hand, trehalose is disaccharide in which two glucose molecules are joined together at their reducing residue, and has three optical isomers, a, α-trehalose, α, β-trehalose and β, β-trehalose. In the natural world, trehalose is present widely in bacteria, plants, and animals, and in the food industry, trehalose has a wide range of applications because of superior characteristics such as relatively low sweetness, anti-aging of starch and prevention of protein degradation during freezing/drying. Furthermore, Korean Patent Publication No. 10-2002-0021320 (published on Mar. 20, 2002) discloses wherein a composition containing trehalose as a sole active ingredient has an effect on the treatment of Sjögren syndrome.
However, there is no report about effects of an ophthalmic composition containing two ingredients, cyclosporine and trehalose, especially on the prevention, reduction, and further treatment of a wide range of dry eyes until now, and moreover, there is no review of a synergistic effect of the two ingredients when combined and the weight ratio or weight % range for showing the synergistic effect.